Abstract

Background:
Severe Plasmodium falciparum malaria is a major cause of death in children. The contribution of the parasite burden to the pathogenesis of severe malaria has been controversial.

Methods:
We documented P. falciparum infection and disease in Tanzanian children followed from birth for an average of 2 years and for as long as 4 years.

Results:
Of the 882 children in our study, 102 had severe malaria, but only 3 had more than two episodes. More than half of first episodes of severe malaria occurred after a second infection. Although parasite levels were higher on average when children had severe rather than mild disease, most children (67 of 102) had high-density infection (>2500 parasites per 200 white cells) with only mild symptoms before severe malaria, after severe malaria, or both. The incidence of severe malaria decreased considerably after infancy, whereas the incidence of high-density infection was similar among all age groups. Infections before and after episodes of severe malaria were associated with similar parasite densities. Nonuse of bed nets, placental malaria at the time of a woman's second or subsequent delivery, high-transmission season, and absence of the sickle cell trait increased severe-malaria risk and parasite density during infections.

Conclusions:
Resistance to severe malaria was not acquired after one or two mild infections. Although the parasite burden was higher on average during episodes of severe malaria, a high parasite burden was often insufficient to cause severe malaria even in children who later were susceptible. The diverging rates of severe disease and high-density infection after infancy, as well as the similar parasite burdens before and after severe malaria, indicate that naturally acquired resistance to severe malaria is not explained by improved control of parasite density. (Funded by the National Institute of Allergy and Infectious Diseases and others.).

Figures

Figure 1. Risk of Severe Malaria and…

Figure 1. Risk of Severe Malaria and Parasite Density

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Panel A shows high-density infections with…

Figure 1. Risk of Severe Malaria and Parasite Density

Panel A shows high-density infections with only mild symptoms (blue circles) that occurred before severe malaria episodes (red circles) in 21 of 102 children, shown according to parasite density and age. Parasite levels during mild high-density infections that occurred before an episode of severe malaria were higher on average than parasite levels during episodes of severe malaria (mean ratio, 8.0; 95% confidence interval [CI], 3.0 to 21.2). The median time from the episode of high-density infection to the first episode of severe malaria was 154 days (interquartile range, 105 to 222). Panel B shows high-density infections with only mild symptoms that occurred after severe malaria episodes in 55 of 102 children, shown according to parasite density and age. Parasite levels during mild high-density infections after severe malaria were higher than parasite levels during episodes of severe malaria (mean ratio, 5.0; 95% CI, 2.9 to 8.6). Panel C shows the mean parasite density of infections in the 9 months before, during, and in the 9 months after a child’s first severe malaria episode. Only children who had at least one episode of parasitemia during the 9 months before and at least one episode of parasitemia during the 9 months after their first episode of severe malaria are included (58 children). The bar within each box indicates the median parasite density, the lower and upper ends of the box indicate the interquartile range, the bars below and above the boxes indicate 5th and 95th percentiles, and the circles indicate outliers.

Panel A shows the cumulative age-specific incidence rate of infections. Panel B shows the cumulative age-specific incidence rate of severe malaria and of high-density infection with no more than mild symptoms. I bars in both panels indicate 95% confidence intervals. Panel C shows the risk of severe malaria during sequential infections. In the fractions above each bar, the numerator is the number of children with severe malaria at that particular infection, and the denominator is the total number of children who had the indicated number of infections. For example, only 25 children had at least 14 infections, and 1 of those children had a first severe malaria episode at the time of that 14th infection.

Figure 3. Discrete and Overlapping Syndromes among…

Figure 3. Discrete and Overlapping Syndromes among Children with Severe Malaria

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Severe anemia was defined…

Figure 3. Discrete and Overlapping Syndromes among Children with Severe Malaria

Severe anemia was defined as a hemoglobin level lower than 5 g per deciliter. Numbers denote the number of children with each condition.